%0 Journal Article
%T Kinome-Wide Functional Genomics Screen Reveals a Novel Mechanism of TNF¦Á-Induced Nuclear Accumulation of the HIF-1¦Á Transcription Factor in Cancer Cells
%A Angela Schoolmeesters
%A Daniel D. Brown
%A Yuriy Fedorov
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0031270
%X Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1¦Á, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1¦Á activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1¦Á under normoxia conditions. TNF¦Á, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1¦Á activity. To improve our understanding of TNF¦Á-mediated regulation of HIF-1¦Á nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging¨Cbased HIF-1¦Á-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNF¦Á signaling (IKK/NF¦ÊB and JNK pathways) has no detrimental effect on HIF-1¦Á accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNF¦Á on HIF-1¦Á stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NF¦ÊB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNF¦Á uses a distinct and complex signaling mechanism to induce accumulation of HIF-1¦Á in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031270